Cholinergic Neurons of the Medial Septum Are Crucial for Sensorimotor Gating

Abstract

Hypofunction of NMDA receptors has been considered a possible cause for the pathophysiology of schizophrenia. More recently, indirect ways to regulate NMDA that would be less disruptive have been proposed and metabotropic glutamate receptor subtype 5 (mGluR5) represents one such candidate. To characterize the cell populations involved, we demonstrated here that knock-out (KO) of mGluR5 in cholinergic, but not glutamatergic or parvalbumin (PV)-positive GABAergic, neurons reduced prepulse inhibition of the startle response (PPI) and enhanced sensitivity to MK801-induced locomotor activity. Inhibition of cholinergic neurons in the medial septum by DREADD (designer receptors exclusively activated by designer drugs) resulted in reduced PPI further demonstrating the importance of these neurons in sensorimotor gating. Volume imaging and quantification were used to compare PV and cholinergic cell distribution, density, and total cell counts in the different cell-type-specific KO lines. Electrophysiological studies showed reduced NMDA receptormediated currents in cholinergic neurons of the medial septum in mGluR5 KO mice. These results obtained from male and female mice indicate that cholinergic neurons in the medial septum represent a key cell type involved in sensorimotor gating and are relevant to pathologies associated with disrupted sensorimotor gating such as schizophrenia.The mechanistic complexity underlying psychiatric disorders remains a major challenge that is hindering the drug discovery process. Here, we generated genetically modified mouse lines to better characterize the involvement of the receptor mGluR5 in the fine-tuning of NMDA receptors, specifically in the context of sensorimotor gating. We evaluated the importance of knocking-out mGluR5 in three different cell types in two brain regions and performed different sets of experiments including behavioral testing and electrophysiological recordings. We demonstrated that cholinergic neurons in the medial septum represent a key cell-type involved in sensorimotor gating. We are proposing that pathologies associated with disrupted sensorimotor gating, such as with schizophrenia, could benefit from further evaluating strategies to modulate specifically cholinergic neurons in the medial septum.

Septohippocampal transmission from parvalbumin-positive neurons features rapid recovery from synaptic depression

“…S2 ). Overall, differences in the localization of and subtypes are consistent with previous studies in rat 15 , 18 , 49 and mouse 50 , 51 . Due to their different localization within MS-DBB and little overlap with anti-PV neurons, neurons appeared to be a distinct subpopulation compared to neurons (Fig.…”

Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition

“…The medial septum participates in PPI mechanisms [ 105 ]. Recently, the septal projection cholinergic neurons have been shown to be a key cell type involved in PPI [ 106 ]. In turn, the pedunculopontine tegmantal area is one of the key structures for PPI [ 36 ] and was shown to be involved in the cardiorespiratory adjustments under increased metabolic demands and hypoxia [ 107 ].…”

The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies

“…There is accumulating evidence to suggest that the MS is involved in the schizophrenia-like phenotypes in animals. For example, sensorimotor gating deficit is evaluated as prepulse inhibition (PPI) and auditory sensory gating in rodent models, which are closely related to theta and gamma band oscillations in the septo-hippocampal axis ( Hajós et al, 2008 ; Jin et al, 2019 ). Psychoactive drugs (PCP, ketamine, MK801 or amphetamine) enhanced gamma oscillations in the HPC and induced schizophrenia-like phenotypes in rats (sensory gating deficits, hyperlocomotion).…”